The project establishes a murine preclinical stroke therapeutics testing site at Yale for the NINDS program Stroke Preclinical Assessment Network (SPAN) to Support Translational Studies for Acute Neuroprotection. A team of investigators including basic scientists studying mechanisms of neurovascular injury after stroke, translational researchers, biomedical imaging specialists, clinical trialists, acute stroke clinicians, and a data manager are forming a highly collaborative and interactive team dedicated to testing candidate neuroprotectants selected by NINDS under the oversight of a national coordinating center. The overall goal is to identify the most promising candidates for novel stroke therapies to then be tested in clinical trials, advancing the care for stroke patients. The team proposes fingolimod as a potential therapy for ischemic stroke to be tested in the network. In Aim 1, the effectiveness of oral fingolimod administered at reperfusion on infarct size and neurobehavioral outcomes in young and aged mice of both sexes with and without tissue plasminogen activator (tPA) will be tested. In Aim 2, the effects of oral fingolimod on stroke outcomes in the setting of hyperglycemia/ diabetes in both sexes with and without tPA will be tested. Aim 3 will test the efficacy and safety of oral fingolimod in the setting of coincident infection. Together these Aims will evaluate the efficacy of fingolimod in improving stroke outcomes in murine models of cerebral ischemia in the setting of clinically-relevant biological variables, comorbidities, and treatments.